OATP2B1 Deficiency Ameliorates Irinotecan-Induced Gastrointestinal Toxicity.

Irinotecan (CPT-11) is a prodrug of the topoisomerase I inhibitor SN-38 used in the treatment of metastatic carcinomas of the colon or rectum. The clinical utility of this drug is hindered by debilitating side effects, most notably, severe gastrointestinal toxicity, which affects up to 40% of patients. Although the accumulation of SN-38 in intestinal enterocytes, following biliary secretion and microbial metabolism of its glucuronide metabolite, is believed to be a critical preceding event to CPT-11-induced toxicity, the transport mechanism involved in this process remains incompletely understood. Here, we tested the hypothesis that the organic anion transporting polypeptide OATP2B1 is an intestinal uptake transporter of SN-38 and a critical determinant of CPT-11-induced toxicity. Mice with Oatp2b1 deficiency experienced milder diarrhea and reduced changes in their intestine length, a known injury marker, compared to wild-type mice when subjected to CPT-11 treatment. These observations were confirmed by a histological examination indicating that damage to intestinal enterocytes was more severe in wild-type mice. The phenotypic alterations in Oatp2b1-deficient mice occurred without substantial changes in measures of systemic exposure to the parent drug, SN-38, or its glucuronide conjugate. Collectively, our study indicates that plasma concentrations of SN-38 are a poor predictive biomarker of CPT-11-induced gastrointestinal toxicity and provides an incentive for the future development of intervention strategies aimed at increasing the tolerance to this clinically important drug with the use of OATP2B1 inhibitors.